Regio- and stereoselective synthesis of spiro-pyrrolidine/pyrrolizidine/ thiazolidine-grafted macrocycles through intramolecular 1,3-dipolar cycloaddition reaction

Article abstract of DOI:10.1016/j.tetlet.2013.08.039

Regioselective synthesis of spiropyrrolidine-grafted 11-membered macrocycle was accomplished through an intramolecular [3+2] cycloaddition of azomethine ylides. The key precursor alkenyl diketone (4a-b) was obtained from simple starting materials. The dipole generated from isatin tethered to O-alkyl enone (4a-b) was reacted intramolecularly to yield the spiropyrrolidine-grafted macrocycles (6a-b). The structures of the cycloadducts were assigned by 2D NMR and confirmed by single crystal analysis.

Full text of DOI:10.1016/j.tetlet.2013.08.039

Tetrahedron Letters 54 (2013) 5744–5747
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Regio- and stereoselective synthesis of spiro-pyrrolidine/pyrrolizi-
dine/thiazolidine-grafted macrocycles through intramolecular 1,3-
dipolar cycloaddition reaction
⇑
S. Purushothaman, R. Prasanna, S. Lavanya, R. Raghunathan
Department of Organic Chemistry, University Of Madras, Guindy Campus, Chennai 600 025, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Regioselective synthesis of spiropyrrolidine-grafted 11-membered macrocycle was accomplished
through an intramolecular [3+2] cycloaddition of azomethine ylides. The key precursor alkenyl diketone
Received 8 May 2013
Revised 7 August 2013
Accepted 9 August 2013
Available online 17 August 2013
(
4a–b) was obtained from simple starting materials. The dipole generated from isatin tethered to O-alkyl
enone (4a–b) was reacted intramolecularly to yield the spiropyrrolidine-grafted macrocycles (6a–b). The
structures of the cycloadducts were assigned by 2D NMR and confirmed by single crystal analysis.
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Macrocycles
Cycloaddition
Spiropyrrolidine
Intramolecular
Regioselective
Spiroheterocycles are very much prevalent as basic skeleton in
many natural products possessing diverse biological activities.
Methods available in the literature for the construction of these
macrocycles involve either complex processes or lengthy proto-
1
1
8
Specifically, spirooxindole derivatives are present in various alka-
cols. Hence, there arises a need to develop a simpler method
for the construction of complex macrocycles of synthetic and bio-
logical importance. 1,3-Dipolar cycloaddition (1,3-DC) reaction is
an elegant and efficient methodology for regio- and stereoselective
loids, and exhibit anticancer, antimalarial,4 antimicrobial, anti-
tubercular, and anti-HIV7 properties. They also act as potential
inhibitors against AChE and MDM28 and show cytotoxicity
2
3
5
6
,9
10
19
against the P388 cell (IC50 = 24
progesterone receptor modulators.
l
g/ml). They find application as
synthesis of structurally complex five-membered heterocycles.
11
These heterocycles, often constitute the core structure of numer-
ous alkaloids and pharmacologically active compounds.
In recent years, macrocyclic compounds are known to have a
variety of application in the field of chemistry, biology, material
science, and nanotechnology.12 Precisely, the nitrogen containing
macrocycles presents a unique structural feature that allows the
molecules to function as receptors in supra molecular chemistry.
These molecules are used as anion and cation receptors in the
molecular recognition process.13 Over a period of years, receptors
that are selective toward the recognition process were also synthe-
In continuation of our research in 1,3-DC reaction of azome-
20
thine ylides, herein we report, the synthesis of spiropyrolidine-
grafted macrocycles via an intramolecular [3+2] cycloaddition
reaction of azomethine ylides. The synthetic plan for the construc-
tion of spiropyrrolidine-grafted macrocycle (6a–b) is shown in
Scheme 1.
Initially, the required monobromo alkenes (2a–b) were pre-
pared from salicylaldehyde by two different routes to get good
yields of the products. For the preparation of O-alkyl enenone 2a,
we first prepared the enone by aldol condensation of salicylalde-
hyde with p-bromoacetophenone. The enone was subsequently re-
acted with 1,4-dibromobutane to give O-alkylated benzylidene
acetophenone 2a (Scheme 2).
1
4
sized. In particular, the macrocycles containing crown ether and
salen units are found to possess good molecular recognition prop-
1
5
erties. The heterocycle bound peptidomimetic macrocycles have
1
6
better pharmacokinetic properties than its peptide analogs.
Overall, these macrocycles or macrolides that represent heterocy-
cle bound natural products, which has good applications in medi-
1
7
cine and supramolecular chemistry has created a considerable
amount of interest in synthetic organic chemistry.
For the preparation of O-alkyl alkenyl ester, we first mono alkyl-
ated salicylaldehyde with dibromobutane which followed Wittig
olefination of aldehyde to give the alkenyl ester (2b) as given be-
low (Scheme 3).
⇑
Corresponding author. Tel.: +91 44 22202811.
E-mail address: ragharaghunathan@yahoo.com (R. Raghunathan).
0
040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.08.039

S. Purushothaman et al. / Tetrahedron Letters 54 (2013) 5744–5747
5745
Intramolecular
O
3
+2 Cycloaddition
O
R
R
Wittig or
O
H
b
O
O
O
Aldol reaction
O
R
Me
O
R
N
R
O
N
H
a
H
O
N
isatin (3)
O
O
O
N
N
O
Br
O
Br
O
O
K CO / DMF
2
3
N-Alkylation
rt, 4-6h
Controlled O-alkylation
monobromoalkene
2a (R = p-Br-C6H4)
2b (R = OEt)
72-78%
Spiropyrrolidine grafted
macrocycles (6a-b)
Alkenyl diketone (4a-b)
4a(R = p-Br-C H )
6
4
Monobromo alkene
,
4d (R = OEt)
(
2a-b)
Scheme 1. Synthetic plan for spiropyrrolidine-grafted macrocycles (6a–b).
Scheme 4. Synthesis of alkyl enenones (4a-b).
COR
O
Me
O
N
(
i) p-Br-acetophenone,
aq.NaOH, rt-heat,
R
Hb
Me
N
O
N
O
Ha
CHO
2
h, 82%, EtOH
R
H
N
O
O
O
N
Br
OH
(ii) 1,4-dibromobutane,
K CO / DMF,
O
PATH A
Me
OH
Salicylaldehyde
Sarcosine (5a)
2
3
Monobromo alkene (2a)
(
1)
rt, 6h, 72%.
R
6a(R = p-Br-C H )
Dry Toluene
6
4
O
6b (R = OEt)
O
O
Dean-Stark, N atm
2
(
FORMED)
Scheme 2. Synthesis of monobromo alkene (2a).
5-6 h, 62-65%
N
O
Ha
Me
PATH B
Me
H N
b
4
a(R = p-Br-C H )
6
4
4
b (R = OEt)
ROC
O
O
O
N
(
i) 1,4-dibromobutane,
H C
2
N
K CO / DMF,
O
Me
2
3
CHO
O
COR
7a(R = p-Br-C
H )
6 4
rt, 65%, 6h.
N
7b (R = OEt)
(
NOT FORMED)
Br
Monobromo alkene (2b)
OH
Salicylaldehyde
1)
(ii) (a) Ph PCHCO
3
2
Et,
O
O
Reflux, Et O,
2
(
88%, 2 h
Scheme 5. Synthesis of spiropyrrolidine-grafted macrocycles (6a–b).
Scheme 3. Synthesis of monobromo alkene (2b).
No steric crowding
H
N
O
The O-alkylated monobromo alkenes 2a–b were then coupled
with isatin to give N-alkyl isatin O-alkyl enone derivatives 4a–b
in excellent yields as shown below (Scheme 4).
Steric hindrance
R
between two keto groups
Me
OH
Hb
R
Me
N
Ha
ROC
Sarcosine
Me
O
H
H
bN
O
a
O
O
Toluene
Toluene
O
The structures of 4a–b were confirmed on the basis of spectro-
scopic data. The geometry of the olefinic double bond was found to
Dean-Stark
N
O
O
N
Dean-Stark
N
O
O
1
Regio isomer 2(7a)
6 4
R = p-Br-C H -
be E as evidenced by H NMR spectra where one of the olefinic pro-
Regio isomer 1(6a)
1
3
tons of 4a appeared as a doublet at d 8.13 (J = 15.9 Hz). In the
NMR spectrum of 4a, the carbonyl carbon’s peaks resonated at
87.7, 157.2, and 155.4 ppm and the remaining carbons exhibited
C
Figure 1. Regioselectivity of intramolecular 1,3-DC reaction.
1
1
peaks at their corresponding ppm values. Similarly, in the H NMR
spectrum of 4b, signals for the protons appeared at the expected d
values.
X
CO H
H
c
X
2
R
H
b
N
H
R
5b-c
The macrocyclic precursor thus prepared is poised to undergo
intramolecular cycloaddition reaction. Thus alkyl enenones teth-
ered to isatin (4a–b) when refluxed with sarcosine in toluene un-
der Dean–Stark reaction condition; generated azomethine ylide
via decaroboxylative condensation which underwent neat intra-
molecular [3+2] cycloaddition reaction with the enone regioselec-
tively to give eleven-membered macrocyclic spiropyrrolidines 6a–
b in moderate yields (Scheme 5).
N
Dry Toluene
O
Ha
O
O
O
Dean-Stark,
N2 atm,
O
N
4
-6 h, 62-68 %
O
N
O
X= -CH - or S
2
4a (R = p-Br-C6H4)
b (R = OEt)
8a-d
4
The structures and the regiochemistry of the cycloadducts 6a–b
Scheme 6. Synthesis of spiropyrrolizidine-grafted macrocycles (8a–d).
2
1a
were unambiguously established by their spectroscopic data.
1
The H NMR spectrum of 6a exhibited one singlet at d 2.10 cor-
responding to the N-methyl group. The benzylic proton H showed
a
The presence of N-methyl and N-methylene carbons was con-
firmed by two signals at 34.8 and 57.4 ppm, respectively, in the
C NMR and DEPT 135 spectrum of 6a. The O-methylene carbon
exhibited a peak at 68.6 ppm and the spiroquaternary carbon
showed a peak at 76.5 ppm. The oxindole carbonyl carbon was
seen at 177.0 ppm. The carbonyl carbon exhibited a peak at
a doublet at d 5.45 (d, J = 10.8 Hz). The coupling constants sug-
gested a trans fusion at the ring junction. A multiplet in the region
1
3
d 4.26–4.35 was observed for H
b
proton. This clearly proved the re-
gio- and stereoselectivity of the cycloaddition reaction. If the other
possible regioisomer 7a had formed, then the benzylic H proton
b
would have shown a doublet instead of a multiplet.
1
97.5 ppm. The rest of the carbons of 6a exhibited peaks at their

5
746
S. Purushothaman et al. / Tetrahedron Letters 54 (2013) 5744–5747
Table 1
Synthesis of pyrrolidine-grafted macrocycles via intramolecular 1,3-DC reaction
Adduct
Structurea
Time (h)
Yieldb (%)
Br
Hb
O
Me
6
a
N
4.2
65
H
a
O
O
N
EtO
O
Hb
Me
N
H
a
6
b
3.5
6.0
5.5
62
64
68
O
O
N
Br
Figure 2. ORTEP diagram of 8b.
Hc
Hb
The dipole generated can react with enone as dipolarophile,
to give two regio-isomers as shown in Figure 1. Thus, the forma-
tion of a single regioisomer 1 may be attributed to strong steric
repulsion between two keto groups during the formation regio-
isomer 2.
8
8
8
a
b
c
N
O
Ha
O
N
O
As an extension of our methodology, the compounds 4a–b
were subjected to [3+2] cycloaddition with cyclic secondary ami-
Hc
EtO
O
no acid,
L-proline/thiazolidine-4-carboxylic acid (5c) to yield the
Hb
spiropyrrolizidine/spirothiazolidine-grafted macrocycles 8a–d in
N
2
1b,c
moderate yields (Scheme 6).
Table 1.
The results are summarized in
Ha
O
The structures of the cycloadducts were established by spectro-
N
1
scopic data. The H NMR spectrum of the cycloadduct 8a exhibited
O
a multiplet in the range d 1.82–2.10 for the pyrrolizidine ring
Br
methylene protons. The benzylic proton H
d 5.88 (J = 11.7 Hz). The coupling constants of H
a
exhibited a doublet at
clearly proved
a
the regio- and stereochemistry of the cycloaddition reaction.
The presence of N-methyl and O-methylene group was con-
firmed by the two signals at 41.3 and 62.5 ppm, respectively, in
Hc
S
Hb
N
6.5
62
13
O
the C NMR and DEPT 135 spectrum of 8a. The carbonyl carbon
Ha
exhibited a peak at 201.3 ppm. The rest of the carbons of 8a
showed peaks at their expected pm values. Finally, the regio- and
stereochemical outcome of the cycloaddition reaction was con-
firmed by single crystal X-ray analysis (Monoclinic, P21/c with
O
O
N
2
2
0
.0571 R value) of the cycloadduct 8b (Fig. 2).
To conclude, the present study describes a highly regioselective
Hc
S
EtO
O
Hb
synthesis of a new class of spiropyrrolidine/spiropyrrolizidine/spi-
ropyrrolothiazole-grafted macrocycles through intramolecular 1,3-
dipolar cycloaddition reaction of azomethine ylides. The dipole
generated via decaroboxylative condensation was intramolecularly
reacted with the suitably placed enone as dipolarophile to give a
variety of spiroheterocycles-grafted macrocycles. This simple
methodology utilizes simple starting materials for the synthesis
of complex spiroheterocycles grafted macrocycles.
N
Ha
8
d
6.0
64
O
N
O
a
Isolated products were characterized by 1H NMR, 13C NMR, mass and X-ray
diffraction analysis.
b
Yields refers to pure isolated products after purification by silica gel column
chromatography.
Acknowledgments
The author S.P. thanks DST, New Delhi for fellowship and DST-
FIST program for the NMR facility. The authors wish to thank Pro-
fessor D. Velmurugan and T. Srinivasan for single crystal X-ray
data. S.P. and R.P. thank CSIR, New Delhi for the award of SRF.
R.R. thanks DST for financial support and UGC for BSR faculty
fellowship.
respective ppm values. Furthermore, the d values of the all the pro-
a b
tons (H , H , O and N-methylene) and carbons (34.8, 57.4, and
6
8.6 ppm) were assigned on the basis of H–H and C, H COSY spec-
trum. Similarly, the structure of 6b was confirmed by spectroscopic
data.

S. Purushothaman et al. / Tetrahedron Letters 54 (2013) 5744–5747
5747
Angew. Chem., Int. Ed. 2012, 51, 9366–9371; (c) Mahapatra, S.; Carter, R. G.
Angew. Chem., Int. Ed. 2012, 51, 7948–7951.
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4
.
.
1. General procedure for the regioselective synthesis of macrocylic pyrrolidines (6a–b,
5
8
L
a–b and 9a–b): A solution of alkyl enenones (4a–b) (0.2 mmol) and sarcosine/
-proline/thiazolidine-4-carboxylic acid (0.2 mmol) was refluxed in dry
toluene under atmosphere for 4–6 h at 110 °C using Dean–Stark
(a) Wong, W. H.; Lim, P. B.; Chuah, C. H. Phytochemistry 1996, 41, 313–315; (b)
Wright, C. W.; Allen, D.; Cai, Y.; Phillipson, J. D.; Said, I. M.; Kirby, G. C.;
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N
2
apparatus. After the completion of reaction as indicated by TLC, toluene was
evaporated under reduced pressure. The crude product was washed with water
and extracted with dichloromethane (4 Â 20 mL). The combined organic layers
5
6
7
8
.
.
.
.
4
were dried (MgSO ) and filtered, concentrated in vacuum. The crude product
was purified by column chromatography using hexane: EtOAc (8:2) mixture as
eluent. (a) Spiropyrrolidine-grafted macrocycle 6a: Yield 65 (210 mg). White
46, 1181–1188.
1
Solid, mp: 257–259 °C. H NMR (300 MHz, CDCl
3
): d 1.76–86 (m, 1H); 1.90–
Ali, A. M.; Ismail, R.; Choon, T. S.; Kumar, R. S.; Osman, H.; Arumugam, N.;
Almansour, A. I.; Elumalai, K.; Singh, A. Bioorg. Med. Chem. Lett. 2012, 22, 508–
2.01 (m, 3H); 2.10 (s, 3H); 3.10 (t, J = 8.4 Hz, 1H); 3.67–3.74 (m, 1H); 3.86–4.04
(
m, 4H); 4.26–4.35 (m, 1H); 5.45 (d, J = 10.8 Hz, 1H); 6.38 (d, J = 7.5 Hz, 1H);
5
11.
6
7
.76–6.81 (m, 1H); 6.84–6.89 (m, 2H); 6.96–7.01 (m, 1H); 7.13–7.18 (m, 2H);
.19–7.22 (m, 2H); 7.36–7.41 (m, 2H); 7.41–7.43 (m, 1H). C NMR (75 MHz,
9
.
Ding, K.; Lu, Y.; Nikolovska-Coleska, Z.; Wang, G.; Qiu, S.; Shangary, S.; Gao, W.;
Qin, D.; Stukey, J.; Krajewski, K.; Roller, P. P.; Wang, S. J. Med. Chem. 2006, 49,
13
3
CDCl ): 25.4, 27.9, 34.8, 40.4, 46.6, 57.3, 57.4, 68.6, 72.2, 76.5, 107.3, 112.0,
3
432–3435.
1
1
C
20.8, 122.5, 126.0, 126.3, 127.2, 127.9, 128.2, 128.8, 129.1, 131.5, 133.6, 136.3,
43.1, 158.3, 177.0, 197.5 ppm. ESI Mass m/z: 531.27 (M +1); Anal. Calcd for
1
1
0. Takada, N.; Suenaga, K.; Yamada, K.; Zheng, S.-Z.; Chen, H.-S.; Uemura, D. Chem.
Lett. 1999, 1025–1026.
+
29
27 2 3
H N O : C, 65.54; H, 5.12; N, 5.27. Found: C, 65.44; H, 5.22; N, 5.36. (b)
1. Fensome, A.; Adams, W. R.; Adams, A. L.; Berrodin, T. J.; Cohen, J.; Huselton, C.;
Illenberger, A.; Karen, J. C.; Hudak, M. A.; Marella, A. G.; Melenski, E. G.;
McComas, C. C.; Mugford, C. A.; Slayeden, O. D.; Yudt, M.; Zhang, J.; Zhang, P.;
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2. (a) Balzani, V.; Credi, A.; Raymo, F. M.; Stoddart, J. F. Angew. Chem., Int. Ed. 2000,
Spiropyrrolizidine grafted macrocycle 8a: Yield 64 (178 mg). White Solid, mp:
1
2
2
1
1
6
3
44–248 °C. H NMR (300 MHz, CDCl ): d 1.68–1.73 (m, 2H); 1.82–1.89 (m,
H); 1.95–2.00 (m, 2H); 2.04–2.10 (m, 2H); 2.34–2.39 (m, 1H); 2.57–2.64 (m,
H); 3.55–3.62 (m, 2H); 3.71–3.75 (m, 1H); 3.96–4.06 (m, 1H); 4.04–4.06 (m,
H); 4.56–4.61 (m, 1H); 5.88 (d, J = 11.7 Hz, 1H); 6.40 (d, J = 7.8 Hz, 1H); 6.76–
.82 (m, 1H); 6.85–6.91 (m, 2H); 7.03–7.14 (m, 3H); 7.19–7.22 (m, 2H); 7.36 (d,
3
J = 7.5 Hz, 1H); 7.51 (d, J = 8.4 Hz, 2H). C NMR (75 MHz, CDCl ): 23.4, 26.4,
1
3
9, 3349–3391; (b) Collier, C. P.; Mattersteig, G.; Wong, E. W.; Luo, Y.; Beverley,
K.; Sampaio, J.; Raymo, F. M.; Stoddart, J. F.; Heath, J. R. Science 2000, 289,
172–1175; (c) Schreiber, S. L. Science 2000, 287, 1964–1969; (d) Wanga, X.-J.;
13
1
2
1
1
8.9, 34.5, 36.8, 42.4, 44.6, 56.6, 69.6, 71.2, 77.5, 110.3, 114.8, 121.8, 123.5,
25.6, 126.6, 128.2, 128.5, 128.9, 129.2, 129.5, 132.5, 133.6, 135.3, 142.1, 159.3,
79.0, 195.5 ppm. ESI Mass m/z: 557.27 (M +1); Anal. Calcd for C31H29BrN O :
2 3
Zhang, J.; Liu, C.-X.; Gong, D.-L.; Zhang, H.; Wang, J.-D.; Yan, Y.-J.; Xiang, W.-S.
Bioorg. Med. Chem. Lett. 2011, 21, 5145–5148; (e) Berg, T. Angew. Chem., Int. Ed.
+
2
003, 42, 2462–2481.
C, 66.79; H, 5.24; N, 5.03. Found: C, 66.88; H, 5.22; N, 5.12. (c)
1
1
1
3. Bazzicalupi, C.; Bencini, A.; Matera, I.; Puccioni, S.; Valtancoli, B. Inorg. Chim.
Acta 2012, 381, 162–169.
4. Camiolo, S.; Gale, P. A.; Hursthouse, M. B.; Light, M. E. Org. Biomol. Chem. 2003,
Spirothiazolidine-grafted macrocycle 8c: Yield 62 (210 mg). White Solid.
1
mp: 244–248 °C. H NMR (300 MHz, CDCl
3
): d 1.78–1.88 (m, 2H); 1.99–2.03
(
(
m, 2H); 2.44–2.47 (m, 1H); 2.57–2.63 (m, 1H); 3.54–3.61 (m, 2H); 3.72–3.73
m, 1H); 4.02–4.06 (m, 2H); 4.14–4.66 (m, 2H); 4.76–4.76 (m, 1H); 5.32 (d,
1
, 741–744.
5. (a) Quinn, P. T.; Atwood, P. D.; Tanski, J. M.; Moore, T. F.; Folmer-Andersen, F. J.
Org. Chem. 2011, 76, 10020–10030; (b) Guo, S.; Wang, G.; Ai, L. Tetrahedron:
Asymmetry 2013, 24, 480–491.
J = 10.2 Hz, 1H); 6.30 (d, J = 7.5 Hz, 1H); 6.86–6.89 (m, 1H); 6.93–6.99 (m, 2H);
.11–7.14 (m, 2H); 7.19–7.22 (m, 3H); 7.33 (d, J = 7.5 Hz, 1H); 7.54 (d,
7
13
J = 8.3 Hz, 2H). C NMR (75 MHz, CDCl
3
): 22.4, 24.3, 28.5, 38.7, 36.8, 43.4, 59.6,
9.4, 70.2, 73.8, 110.3, 114.8, 121.8, 123.5, 125.6, 126.6, 127.5, 127.9, 128.2,
28.5, 133.5, 134.6, 134.3, 140.1, 157.3, 176.0, 193.4 ppm. ESI Mass: m/z:
1
1
1
6. Davis, M. R.; Singh, E. K.; Wahyudi, H.; Alexander, L. D.; Kunicki, J. B.; Nazarova,
L. A.; Fairweather, K. A.; Giltrap, A. M.; Jolliffe, K. A.; McAlpine, S. R. Tetrahedron
6
1
5
2
012, 68, 1029–1051.
+
2 3
75.55 (M +1); Anal. Calcd for C30H27BrN O S: C, 62.61; H, 4.73; N, 4.87.
7. (a) Wagh, B.; Paul, T.; Glassford, I.; DeBrosse, C.; Klepacki, D.; Small, M. C.;
MacKerell, A. D., Jr.; Andrade, R. B. ACS Med. Chem. Lett. 2012, 3, 1013–1018; (b)
Sato, S.; Iwata, F.; Yamada, S.; Katayama, M. J. Nat. Prod. 2012, 75, 1974–1982.
8. (a) Smith, III. A. B.; Basu, K.; Bosanac, T. J. Am. Chem. Soc. 2007, 129, 14872–
Found: C, 62.72; H, 4.87; N, 4.85.
22. Narayanan, S.; Srinivasan, T.; Purushothaman, S.; Raghunathan, R.;
Velmurugan, D. Acta Cryst. 2013, E69, o23–o24.
1
4874; (b) Frost, J. R.; Pearson, C. M.; Snaddon, T. N.; Booth, R. A.; Ley, S. V.